CN103265457B - A kind of synthetic method of (R)-4-aminophenethyl-(2-hydroxyl-2-styroyl)-t-butyl carbamate - Google Patents
A kind of synthetic method of (R)-4-aminophenethyl-(2-hydroxyl-2-styroyl)-t-butyl carbamate Download PDFInfo
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- CN103265457B CN103265457B CN201310163326.1A CN201310163326A CN103265457B CN 103265457 B CN103265457 B CN 103265457B CN 201310163326 A CN201310163326 A CN 201310163326A CN 103265457 B CN103265457 B CN 103265457B
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- nitrophenyl
- hydroxyl
- styroyl
- butyl carbamate
- phenylethyl alcohol
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- 238000010189 synthetic method Methods 0.000 title claims abstract description 31
- 229940067107 phenylethyl alcohol Drugs 0.000 claims abstract description 20
- NDXLKCBBPVHYSO-UHFFFAOYSA-N 2-(4-nitrophenyl)acetaldehyde Chemical compound [O-][N+](=O)C1=CC=C(CC=O)C=C1 NDXLKCBBPVHYSO-UHFFFAOYSA-N 0.000 claims abstract description 17
- CRJFHXYELTYDSG-UHFFFAOYSA-N 1-(4-nitrophenyl)ethanol Chemical compound CC(O)C1=CC=C([N+]([O-])=O)C=C1 CRJFHXYELTYDSG-UHFFFAOYSA-N 0.000 claims abstract description 10
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims abstract description 9
- 239000012467 final product Substances 0.000 claims abstract description 5
- 238000009833 condensation Methods 0.000 claims abstract description 3
- 230000005494 condensation Effects 0.000 claims abstract description 3
- 238000006243 chemical reaction Methods 0.000 claims description 89
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 56
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 39
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 36
- 238000003756 stirring Methods 0.000 claims description 29
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 28
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 26
- 239000012043 crude product Substances 0.000 claims description 24
- 239000002904 solvent Substances 0.000 claims description 22
- 239000007788 liquid Substances 0.000 claims description 21
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 16
- 239000000706 filtrate Substances 0.000 claims description 15
- 229910052757 nitrogen Inorganic materials 0.000 claims description 15
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 claims description 10
- 230000000694 effects Effects 0.000 claims description 10
- 239000012074 organic phase Substances 0.000 claims description 10
- 239000001257 hydrogen Substances 0.000 claims description 9
- 229910052739 hydrogen Inorganic materials 0.000 claims description 9
- 239000012279 sodium borohydride Substances 0.000 claims description 9
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 9
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 8
- 239000012065 filter cake Substances 0.000 claims description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 8
- FIYYMXYOBLWYQO-UHFFFAOYSA-N ortho-iodylbenzoic acid Chemical group OC(=O)C1=CC=CC=C1I(=O)=O FIYYMXYOBLWYQO-UHFFFAOYSA-N 0.000 claims description 7
- 238000006722 reduction reaction Methods 0.000 claims description 7
- 230000002829 reductive effect Effects 0.000 claims description 7
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 5
- 235000019270 ammonium chloride Nutrition 0.000 claims description 5
- 238000001953 recrystallisation Methods 0.000 claims description 5
- 229920006395 saturated elastomer Polymers 0.000 claims description 5
- 238000000967 suction filtration Methods 0.000 claims description 5
- 238000005406 washing Methods 0.000 claims description 5
- 238000005576 amination reaction Methods 0.000 claims description 4
- 239000012141 concentrate Substances 0.000 claims description 4
- 238000000034 method Methods 0.000 claims description 3
- 230000001590 oxidative effect Effects 0.000 claims description 3
- 239000012295 chemical reaction liquid Substances 0.000 claims description 2
- 238000002386 leaching Methods 0.000 claims description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 2
- 238000006268 reductive amination reaction Methods 0.000 claims description 2
- 238000006467 substitution reaction Methods 0.000 claims description 2
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims 2
- 239000000047 product Substances 0.000 abstract description 9
- 230000015572 biosynthetic process Effects 0.000 abstract description 6
- 238000003786 synthesis reaction Methods 0.000 abstract description 6
- 238000003912 environmental pollution Methods 0.000 abstract description 4
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- 239000003814 drug Substances 0.000 abstract description 3
- OUUQCZGPVNCOIJ-UHFFFAOYSA-N hydroperoxyl Chemical compound O[O] OUUQCZGPVNCOIJ-UHFFFAOYSA-N 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 36
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 15
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 13
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 7
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 6
- 238000001514 detection method Methods 0.000 description 6
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 5
- 239000003153 chemical reaction reagent Substances 0.000 description 5
- 239000003795 chemical substances by application Substances 0.000 description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 4
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 4
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 4
- JHUUPUMBZGWODW-UHFFFAOYSA-N 3,6-dihydro-1,2-dioxine Chemical compound C1OOCC=C1 JHUUPUMBZGWODW-UHFFFAOYSA-N 0.000 description 3
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 3
- 239000007868 Raney catalyst Substances 0.000 description 3
- 229910000564 Raney nickel Inorganic materials 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- 239000012230 colorless oil Substances 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 150000002431 hydrogen Chemical class 0.000 description 3
- PBAPPPCECJKMCM-IBGZPJMESA-N mirabegron Chemical compound S1C(N)=NC(CC(=O)NC=2C=CC(CCNC[C@H](O)C=3C=CC=CC=3)=CC=2)=C1 PBAPPPCECJKMCM-IBGZPJMESA-N 0.000 description 3
- 229960001551 mirabegron Drugs 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- 238000011084 recovery Methods 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 2
- 206010020853 Hypertonic bladder Diseases 0.000 description 2
- 102000004877 Insulin Human genes 0.000 description 2
- 108090001061 Insulin Proteins 0.000 description 2
- 208000009722 Overactive Urinary Bladder Diseases 0.000 description 2
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 2
- 150000001408 amides Chemical class 0.000 description 2
- 238000009835 boiling Methods 0.000 description 2
- 229960001701 chloroform Drugs 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 229940125396 insulin Drugs 0.000 description 2
- 239000000543 intermediate Substances 0.000 description 2
- 239000012280 lithium aluminium hydride Substances 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 208000020629 overactive bladder Diseases 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- 239000012286 potassium permanganate Chemical group 0.000 description 2
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 2
- LEHBURLTIWGHEM-UHFFFAOYSA-N pyridinium chlorochromate Chemical compound [O-][Cr](Cl)(=O)=O.C1=CC=[NH+]C=C1 LEHBURLTIWGHEM-UHFFFAOYSA-N 0.000 description 2
- 230000035484 reaction time Effects 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 238000007086 side reaction Methods 0.000 description 2
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 description 1
- RKMGAJGJIURJSJ-UHFFFAOYSA-N 2,2,6,6-tetramethylpiperidine Chemical compound CC1(C)CCCC(C)(C)N1 RKMGAJGJIURJSJ-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- PNEYBMLMFCGWSK-UHFFFAOYSA-N Alumina Chemical compound [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- GSNUFIFRDBKVIE-UHFFFAOYSA-N DMF Natural products CC1=CC=C(C)O1 GSNUFIFRDBKVIE-UHFFFAOYSA-N 0.000 description 1
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 206010070834 Sensitisation Diseases 0.000 description 1
- NSOXQYCFHDMMGV-UHFFFAOYSA-N Tetrakis(2-hydroxypropyl)ethylenediamine Chemical compound CC(O)CN(CC(C)O)CCN(CC(C)O)CC(C)O NSOXQYCFHDMMGV-UHFFFAOYSA-N 0.000 description 1
- 208000000921 Urge Urinary Incontinence Diseases 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000003178 anti-diabetic effect Effects 0.000 description 1
- 239000003472 antidiabetic agent Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 229910000085 borane Inorganic materials 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- -1 concentrated Substances 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
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- 230000002124 endocrine Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000011049 filling Methods 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 230000003914 insulin secretion Effects 0.000 description 1
- 238000004811 liquid chromatography Methods 0.000 description 1
- 208000030159 metabolic disease Diseases 0.000 description 1
- 230000027939 micturition Effects 0.000 description 1
- 231100000150 mutagenicity / genotoxicity testing Toxicity 0.000 description 1
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- DCKVFVYPWDKYDN-UHFFFAOYSA-L oxygen(2-);titanium(4+);sulfate Chemical compound [O-2].[Ti+4].[O-]S([O-])(=O)=O DCKVFVYPWDKYDN-UHFFFAOYSA-L 0.000 description 1
- MUJIDPITZJWBSW-UHFFFAOYSA-N palladium(2+) Chemical compound [Pd+2] MUJIDPITZJWBSW-UHFFFAOYSA-N 0.000 description 1
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 description 1
- 239000012450 pharmaceutical intermediate Substances 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
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- 231100000614 poison Toxicity 0.000 description 1
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- 230000001737 promoting effect Effects 0.000 description 1
- PXDRFTPXHTVDFR-UHFFFAOYSA-N propane;titanium(4+) Chemical compound [Ti+4].C[CH-]C.C[CH-]C.C[CH-]C.C[CH-]C PXDRFTPXHTVDFR-UHFFFAOYSA-N 0.000 description 1
- 230000000452 restraining effect Effects 0.000 description 1
- SMQUZDBALVYZAC-UHFFFAOYSA-N salicylaldehyde Chemical compound OC1=CC=CC=C1C=O SMQUZDBALVYZAC-UHFFFAOYSA-N 0.000 description 1
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- 230000008313 sensitization Effects 0.000 description 1
- 210000002460 smooth muscle Anatomy 0.000 description 1
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 1
- SUKJFIGYRHOWBL-UHFFFAOYSA-N sodium hypochlorite Chemical compound [Na+].Cl[O-] SUKJFIGYRHOWBL-UHFFFAOYSA-N 0.000 description 1
- PODWXQQNRWNDGD-UHFFFAOYSA-L sodium thiosulfate pentahydrate Chemical compound O.O.O.O.O.[Na+].[Na+].[O-]S([S-])(=O)=O PODWXQQNRWNDGD-UHFFFAOYSA-L 0.000 description 1
- 239000012321 sodium triacetoxyborohydride Substances 0.000 description 1
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- 229910000348 titanium sulfate Inorganic materials 0.000 description 1
- XJDNKRIXUMDJCW-UHFFFAOYSA-J titanium tetrachloride Chemical compound Cl[Ti](Cl)(Cl)Cl XJDNKRIXUMDJCW-UHFFFAOYSA-J 0.000 description 1
- UORVGPXVDQYIDP-UHFFFAOYSA-N trihydridoboron Substances B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 description 1
- RMUKCGUDVKEQPL-UHFFFAOYSA-K triiodoindigane Chemical compound I[In](I)I RMUKCGUDVKEQPL-UHFFFAOYSA-K 0.000 description 1
- 206010046494 urge incontinence Diseases 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
The invention provides the synthetic method of one (R)-4-aminophenethyl-(2-hydroxyl-2-styroyl)-t-butyl carbamate, belong to technical field of medicine synthesis.It solve synthetic method product yield of the prior art low, the problem such as the loaded down with trivial details and environmental pollution for the treatment of step is serious.Synthesis step of the present invention comprises: first the hydroxyl oxygen on p-nitrophenyl ethanol is changed into aldehyde radical and obtain p-nitrophenyl acetaldehyde; The amino on (R)-2-amino-1-phenylethyl alcohol and the aldehyde radical dehydrating condensation on p-nitrophenyl acetaldehyde is made to reduce (R)-2-p-nitrophenyl ethylamino--1-phenylethyl alcohol again; With (Boc)
2o replaces the amino on (R)-2-p-nitrophenyl ethylamino--1-phenylethyl alcohol; Finally the nitroreduction on (R)-4-nitrophenethyl-(2-hydroxyl-2-styroyl)-t-butyl carbamate is become amino and obtain final product.Synthetic method production cost of the present invention is low, and product yield is high, and environmental pollution is little.
Description
Technical field
The present invention relates to a kind of synthetic method of pharmaceutical intermediate, particularly relate to the synthetic method of one (R)-4-aminophenethyl-(2-hydroxyl-2-styroyl)-t-butyl carbamate, belong to technical field of medicine synthesis.
Background technology
Through data presentation, at present by the large contingent of overactive bladder puzzlement, as just about there are 3,300 ten thousand people in the U.S..Use Mirabegron that detrusor smooth muscle can be made to relax and become lax in the storage of filling of bladder-urination cycle, thus promote to increase bladder capacity, therefore Mirabegron is used to treat the overactive bladder with urge incontinence, urgent urination, frequency symptoms.In addition, along with the raising of people's social and economic activities, diabetes become the endocrine metabolism disease of a kind of common puzzlement people gradually.Find the more general antidiabetic oral medicine of amide derivatives and insulin preparation after deliberation, there is the effect better promoting insulin secretion and the effect strengthening insulin receptivity, thus more effectively can control blood sugar.
And (R)-4-aminophenethyl-(2-hydroxyl-2-styroyl)-t-butyl carbamate, be the synthesis important intermediate of Mirabegron and the important intermediate of synthesizing amide derivative, its chemical structural formula is:
About the document of synthesis (R)-4-aminophenethyl-(2-hydroxyl-2-styroyl)-t-butyl carbamate has Chinese patent application file (publication number: CN1218045A) in prior art, it relates to the synthetic method that one prepares (R)-4-aminophenethyl-(2-hydroxyl-2-styroyl)-t-butyl carbamate, and this synthetic route is:
There is following problem in this synthetic method:
1), employ poisonous S-Styrene oxide 98min. reagent in this synthetic method, this reagent has restraining effect to nervus centralis, and have stimulation and sensitization to skin, positive findings appears in multiple mutagenicity test, unfavorable to operator.
2), employ expensive S-Styrene oxide 98min. reagent in this synthetic method, and need column chromatography for separation after completion of the reaction, cause production cost high.
3), after completion of the reaction reaction solution just need can obtain sterling through twice column chromatography for separation, post-processing step is loaded down with trivial details and can produce a large amount of three wastes, and product yield is low.
Summary of the invention
The object of the invention is to for exist in prior art deficiency, provide a kind of yield high, cost is low, the method for synthesis (R)-4-aminophenethyl-(2-hydroxyl-2-styroyl)-t-butyl carbamate that environmental pollution is little.
Above-mentioned purpose of the present invention can be realized by following technical proposal: a kind of synthetic method of (R)-4-aminophenethyl-(2-hydroxyl-2-styroyl)-t-butyl carbamate, and this synthetic method comprises the following steps:
S1, oxidizing reaction: with p-nitrophenyl ethanol for raw material, make itself and oxygenant carry out oxidizing reaction in a solvent, makes the hydroxyl on described p-nitrophenyl ethanol be oxidized to aldehyde radical, obtain p-nitrophenyl acetaldehyde.
S2, reduction amination: above-mentioned obtained p-nitrophenyl acetaldehyde is carried out reductive amination process with (R)-2-amino-1-phenylethyl alcohol under the effect of reductive agent, make the amino on (R)-2-amino-1-phenylethyl alcohol and the aldehyde radical dehydrating condensation on p-nitrophenyl acetaldehyde, after reduction, obtain (R)-2-p-nitrophenyl ethylamino--1-phenylethyl alcohol.
S3, substitution reaction: by above-mentioned obtained (R)-2-p-nitrophenyl ethylamino--1-phenylethyl alcohol and (Boc)
2o reacts, and makes amino quilt (Boc) on (R)-2-p-nitrophenyl ethylamino--1-phenylethyl alcohol
2o replaces (R)-4-nitrophenethyl-(2-hydroxyl-2-styroyl)-t-butyl carbamate.
S4, reduction reaction: above-mentioned obtained (R)-4-nitrophenethyl-(2-hydroxyl-2-styroyl)-t-butyl carbamate is dissolved in solvent, under the effect of catalyzer and hydrogen, make the nitro on (R)-4-nitrophenethyl-(2-hydroxyl-2-styroyl)-t-butyl carbamate be reduced into amino, obtain final product (R)-4-aminophenethyl-(2-hydroxyl-2-styroyl)-t-butyl carbamate.
In the synthetic method of above-mentioned (R)-4-aminophenethyl-(2-hydroxyl-2-styroyl)-t-butyl carbamate; described step S1 specifically comprises the steps: under the protection of nitrogen; p-nitrophenyl ethanol and oxygenant are joined forming reactions liquid in solvent; by reaction solution return stirring to reacting completely; reaction solution after reacting completely is down to room temperature; suction filtration obtains filter cake and filtrate, washing leaching cake, and merging, concentrated filtrate obtain p-nitrophenyl acetaldehyde.
As preferably, oxygenant described in step S1 is adjacent iodoxybenzoic acid, potassium permanganate, Manganse Dioxide, Dai Si-Martin's oxygenant, 2, one or more in 2,6,6-tetramethyl piperidine oxide compound, pyridinium chloro-chromate, clorox, oxygen, nitric acid, aluminium sesquioxide.
Wherein, the mol ratio of described oxygenant and p-nitrophenyl ethanol is (2 ~ 4): 1.
Further preferably, the oxygenant described in step S1 is adjacent iodoxybenzoic acid.Adjacent iodoxybenzoic acid is compared with other oxygenants, and react comparatively rapid in the present reaction, aftertreatment is simpler, makes that this reactor product yield is high and side reaction is few, is almost quantitative reaction, and usage quantity is low thus reduce production cost.
As preferably, the solvent described in step S1 be in ethyl acetate, Isosorbide-5-Nitrae-dioxane, trichloromethane, 1,2-ethylene dichloride, acetone, benzene, acetonitrile, tetrahydrofuran (THF), toluene one or more.
Further preferably, the solvent described in step S1 is ethyl acetate, 1,2-ethylene dichloride.Ethyl acetate and 1,2-ethylene dichloride and other solvent phase ratios, have the reaction times in the present reaction fast, yield is high, and impurities left is few, the simple and low cost and other advantages of aftertreatment.
In the synthetic method of above-mentioned (R)-4-aminophenethyl-(2-hydroxyl-2-styroyl)-t-butyl carbamate; described step S2 specifically comprises the steps: under the protection of nitrogen; the solvent being dissolved with p-nitrophenyl acetaldehyde obtained in step S1 is added drop-wise to forming reactions liquid in (R)-2-amino-1-phenylethyl alcohol; under stirring, reductive agent is joined in reaction solution, be stirred to and react completely.Saturated aqueous ammonium chloride is added drop-wise in the reaction solution reacted completely and carries out cancellation reaction, then wash with water, separate organic phase.Obtaining crude product by dry for organic phase, concentrated, crude product recrystallization obtains (R)-2-p-nitrophenyl ethylamino--1-phenylethyl alcohol.
Wherein substance reaction large for expression activitiy can fall by cancellation reaction, prevents side reaction.
As preferably, the solvent described in step S2 is one or more in methylene dichloride, tetrahydrofuran (THF), ethanol, ethylene dichloride, methyl alcohol, Virahol, Isosorbide-5-Nitrae-dioxane, normal heptane, formic acid, toluene, acetonitrile, acetic acid, hexanaphthene, water.
Further preferably, the solvent described in step S2 is methylene dichloride, tetrahydrofuran (THF).Methylene dichloride and tetrahydrofuran (THF), relative to other solvents, have cost low, and aftertreatment is simple in the present reaction, and product loss is little, yield advantages of higher.
As preferably, the reductive agent described in step S2 is one or more in sodium borohydride, metallic nickel, hydrogen, titanium tetrachloride, Lithium Aluminium Hydride, sodium cyanoborohydride, sodium triacetoxy borohydride, borine, tetra isopropyl titanium.
Wherein, the reductive agent described in step S2 is (1 ~ 3) with the mol ratio of (R)-2-amino-1-phenylethyl alcohol: 1.
Further preferably, the reductive agent described in step S2 is sodium borohydride.Sodium borohydride is applied very extensive in the industrial production, and cheap and easy to get, its activity is moderate, and aftertreatment is in the reaction simple, can improve the yield of product.
In the synthetic method of above-mentioned (R)-4-aminophenethyl-(2-hydroxyl-2-styroyl)-t-butyl carbamate, described step S3 specifically comprises the steps: (R)-2-p-nitrophenyl ethylamino--1-phenylethyl alcohol obtained in step S2 to be dissolved in solvent, stirs lower to (Boc)
2o is added drop-wise in solvent, reaction solution is risen to room temperature, be stirred to and react completely, the reaction solution reacted completely directly is concentrated to obtain crude product, and crude product recrystallization obtains final product (R)-4-nitrophenethyl-(2-hydroxyl-2-styroyl)-t-butyl carbamate.
As preferably, solvent described in step S3 is tetrahydrofuran (THF), 1, one or more in 4-dioxane, methyl alcohol, the trimethyl carbinol, acetone, ethanol, n-propyl alcohol, Virahol, DMF, acetonitrile, 1,2-glycol dimethyl ether, normal hexane, methylene dichloride, water.
Further preferably, the solvent described in step S3 is tetrahydrofuran (THF), methyl alcohol.Tetrahydrofuran (THF) and methyl alcohol boiling point low, aftertreatment is in the reaction simple, can improve product yield.
Wherein, (Boc) described in step S3
2o with the mol ratio of (R)-2-p-nitrophenyl ethylamino--1-phenylethyl alcohol is: (1 ~ 3): 1.
In the synthetic method of above-mentioned (R)-4-aminophenethyl-(2-hydroxyl-2-styroyl)-t-butyl carbamate, described step S4 specifically comprises the steps: (R)-4-nitrophenethyl-(2-hydroxyl-2-styroyl)-t-butyl carbamate obtained in step S3 to be dissolved in solvent forming reactions liquid, under the effect of catalyzer and hydrogen, under the condition of room temperature, stirring reaction liquid is to reacting completely, solubilizing agent dilute reaction solution, use filtered off through Celite catalyzer, the filtrate of gained is concentrated to obtain (R)-4-aminophenethyl-(2-hydroxyl-2-styroyl)-t-butyl carbamate.
As preferably, the solvent described in step S4 is one or more in methyl alcohol, ethanol, Virahol, the trimethyl carbinol, water, benzene, DMF, toluene, chloroform, acetonitrile, ethyl acetate, tetrahydrofuran (THF), acetone, acetic acid.
Further preferably, the solvent described in step S4 is methyl alcohol.Relative to other solvents, methyl alcohol polarity is large, good to substrate solvability, low price, and boiling point is low and be easy to recovery in the present reaction.
As preferably, catalyzer described in step S4 is one or more in palladium charcoal, Raney nickel, hydrazine hydrate, anhydrous hydrazine, Sulfothiorine, sodium borohydride, iron powder, zinc powder, indium triiodide, Lithium Aluminium Hydride, N, N '-two salicylic aldehyde quadrol palladium (II), palladium chloride, titanium sulfate, titanous chloride.
Further preferably, the catalyzer described in step S4 is palladium charcoal.Compared with other catalyzer, the palladium charcoal reaction times is in the present invention short, and yield is high, is easy to be separated with reaction solution and can recovery repeatedly.
The chemical equation of synthetic method of the present invention is as follows:
In sum, the present invention has the following advantages:
1, the crude product in synthetic method of the present invention does not need purifying just reducible amination, and reagent used and solvent are regular industrial specification, and be applicable to industrialized production, environmental pollution is little, and processing safety is high.
2, in synthetic method of the present invention with adjacent iodoxybenzoic acid for oxygenant, oxidation products directly and next step raw material reduction amination, the raw material used and reagent cheap and easy to get, cost is low.
3, adopt synthetic method post-reaction treatment of the present invention simple, yield is high, purity Gao Keda more than 99%, good product quality, and recrystallization sterling.
Accompanying drawing explanation
Fig. 1 is the liquid chromatogram of (R)-4-aminophenethyl-(2-hydroxyl-2-the styroyl)-t-butyl carbamate adopting synthetic method of the present invention to prepare.
Embodiment
Be below specific embodiments of the invention and by reference to the accompanying drawings, technical scheme of the present invention is further described, but the present invention be not limited to these embodiments.
Embodiment 1
Under the protection of nitrogen, 1.67g p-nitrophenyl ethanol and the adjacent iodoxybenzoic acid of 7g are dissolved in forming reactions liquid in 50mL ethyl acetate, successively by little for reaction solution return stirring 1 complete up to TLC detection reaction.The reaction solution reacted completely is down to room temperature, and suction filtration obtains filtrate and filter cake.Filter cake 20mL ethyl acetate washes twice to obtain p-nitrophenyl acetaldehyde, filtrate merges, concentrated after apply mechanically.
When 0 DEG C, under the protection of nitrogen, by 1.37g(R)-2-amino-1-phenylethyl alcohol adds in 100mL there-necked flask, then the 50mL methylene dichloride being dissolved with described p-nitrophenyl acetaldehyde crude product is added drop-wise to forming reactions liquid in there-necked flask.Under the protection of nitrogen, continue stirring 1 hour, while stirring 0.76g sodium borohydride is added in reaction solution.Reaction solution stirs 3 little complete up to TLC detection reaction under the condition of 0 DEG C.In the reaction solution of complete reaction, drip 10mL saturated aqueous ammonium chloride carry out cancellation reaction, then add the water washing twice of 40mL respectively, separate organic phase.Organic phase is used 5g anhydrous sodium sulfate drying, concentrate to obtain crude product.Crude product obtains 2.5g (R)-2-p-nitrophenyl ethylamino--1-phenylethyl alcohol by normal heptane and re-crystallizing in ethyl acetate again.
When 0 DEG C, (the R)-2-p-nitrophenyl ethylamino--1-phenylethyl alcohol described in 2.5g is dissolved in the tetrahydrofuran (THF) of 50mL, by 2.86g(Boc under stirring)
2o is added drop-wise to forming reactions liquid in tetrahydrofuran (THF), reaction solution is risen to stirring at room temperature to reacting completely, and the reaction solution reacted completely directly is concentrated to obtain crude product.Crude product normal heptane and re-crystallizing in ethyl acetate obtain 3.0g (R)-4-nitrophenethyl-(2-hydroxyl-2-styroyl)-t-butyl carbamate.Purity is 99.85%, and chiral purity is 99.0%, and yield is 89.3%.
(R)-4-nitrophenethyl described in 3.0g-(2-hydroxyl-2-styroyl)-t-butyl carbamate is dissolved in the anhydrous methanol forming reactions liquid of 15mL.Add in reaction solution by the palladium charcoal of 0.3g5%, under hydrogen and room temperature condition, stirring 16 is little detects to reacting completely up to TLC.Add 15mL anhydrous methanol dilute reaction solution, with filtered off through Celite palladium charcoal, the filtrate of gained is concentrated that colorless oil 2.6g is (R)-4-aminophenethyl-(2-hydroxyl-2-styroyl)-t-butyl carbamate.Purity is 99.29%, yield 94.2%, chiral purity 99.58%.
Embodiment 2
Under the protection of nitrogen, 3.34g p-nitrophenyl ethanol and 10.1g potassium permanganate are dissolved in 100mL1 successively, forming reactions liquid in 4-dioxane, by little for reaction solution return stirring 3 complete up to TLC detection reaction.The reaction solution reacted completely is down to room temperature, and suction filtration obtains filtrate and filter cake.Filter cake 40mL1,4-dioxane washes twice to obtain p-nitrophenyl acetaldehyde, filtrate merges, concentrated after apply mechanically.
When 0 DEG C, under the protection of nitrogen, by 2.7g(R)-2-amino-1-phenylethyl alcohol adds in 250mL there-necked flask, then the 100mL tetrahydrofuran (THF) being dissolved with described p-nitrophenyl acetaldehyde crude product is added drop-wise to forming reactions liquid in there-necked flask.Under the protection of nitrogen, continue stirring 2 hours, while stirring 2.3g metallic nickel is added in reaction solution.Reaction solution stirs 3 little complete up to TLC detection reaction under the condition of 0 DEG C.In the reaction solution of complete reaction, drip 20mL saturated aqueous ammonium chloride carry out cancellation reaction, then add the water washing twice of 80mL respectively, separate organic phase.Organic phase is used 10g anhydrous sodium sulfate drying, concentrate to obtain crude product.Crude product obtains 4.98g (R)-2-p-nitrophenyl ethylamino--1-phenylethyl alcohol by normal heptane and re-crystallizing in ethyl acetate again.
When 0 DEG C, (the R)-2-p-nitrophenyl ethylamino--1-phenylethyl alcohol described in 4.98g is dissolved in the methyl alcohol of 100mL, by 5.48g(Boc under stirring)
2o is added drop-wise to forming reactions liquid in methyl alcohol, reaction solution is risen to stirring at room temperature to reacting completely, and the reaction solution reacted completely directly is concentrated to obtain crude product.Crude product normal heptane and re-crystallizing in ethyl acetate obtain 5.8g (R)-4-nitrophenethyl-(2-hydroxyl-2-styroyl)-t-butyl carbamate.Purity is 98.92%, and chiral purity is 99.60%, two step total recoverys is 74.32%.
(R)-4-nitrophenethyl described in 5.8g-(2-hydroxyl-2-styroyl)-t-butyl carbamate is dissolved in the ethanol forming reactions liquid of 25mL.Add in reaction solution by the Raney nickel of 0.5g, under hydrogen and room temperature condition, stirring 16 is little detects to reacting completely up to TLC.Add 25mL alcohol dilution reaction solution, use filtered off through Celite Raney nickel, the filtrate of gained is concentrated that colorless oil 4.9g is (R)-4-aminophenethyl-(2-hydroxyl-2-styroyl)-t-butyl carbamate.Purity is 99.65%, yield 72.9%, chiral purity 99.12%.
Embodiment 3
Under the protection of nitrogen, 2.5g p-nitrophenyl ethanol and 3.1g Manganse Dioxide are dissolved in 80mL1 successively, forming reactions liquid in 2 ethylene dichloride, by little for reaction solution return stirring 2 complete up to TLC detection reaction.The reaction solution reacted completely is down to room temperature, and suction filtration obtains filtrate and filter cake.Filter cake 30mL1,2 ethylene dichloride wash twice to obtain p-nitrophenyl acetaldehyde, filtrate merges, concentrated after apply mechanically.
When 0 DEG C, under the protection of nitrogen, by 2.05g(R)-2-amino-1-phenylethyl alcohol adds in 250mL there-necked flask, then the 80mL tetrahydrofuran (THF) being dissolved with described p-nitrophenyl acetaldehyde crude product is added drop-wise to forming reactions liquid in there-necked flask.Under the protection of nitrogen, continue stirring 2 hours, while stirring 1.03g sodium borohydride is added in reaction solution.Reaction solution stirs 3 little complete up to TLC detection reaction under the condition of 0 DEG C.In the reaction solution of complete reaction, drip 15mL saturated aqueous ammonium chloride carry out cancellation reaction, then add the water washing twice of 60mL respectively, separate organic phase.Organic phase is used 7g anhydrous sodium sulfate drying, concentrate to obtain crude product.Crude product obtains 3.7g (R)-2-p-nitrophenyl ethylamino--1-phenylethyl alcohol by normal heptane and re-crystallizing in ethyl acetate again.
When 0 DEG C, (the R)-2-p-nitrophenyl ethylamino--1-phenylethyl alcohol described in 3.7g is dissolved in the methylene dichloride of 80mL, by 4.16g(Boc under stirring)
2o is added drop-wise to forming reactions liquid in methylene dichloride, reaction solution is risen to stirring at room temperature to reacting completely, and the reaction solution reacted completely directly is concentrated to obtain crude product.Crude product normal heptane and re-crystallizing in ethyl acetate obtain 4.48g (R)-4-nitrophenethyl-(2-hydroxyl-2-styroyl)-t-butyl carbamate.Purity is 99.06%, and chiral purity is 99.95%, and yield is 76.8%.
(R)-4-nitrophenethyl described in 4.48g-(2-hydroxyl-2-styroyl)-t-butyl carbamate is dissolved in the Virahol forming reactions liquid of 20mL.Add in reaction solution by the palladium charcoal of 0.4g5%, under hydrogen and room temperature condition, stirring 16 is little detects to reacting completely up to TLC.Add 20mL isopropanol reaction solution, with filtered off through Celite palladium charcoal, the filtrate of gained is concentrated that colorless oil 3.8g is (R)-4-aminophenethyl-(2-hydroxyl-2-styroyl)-t-butyl carbamate.Purity is 99.86%, yield 75.4%, chiral purity 99.63%.
Extract (R)-4-aminophenethyl-(2-hydroxyl-2-the styroyl)-t-butyl carbamate sample adopting synthetic method of the present invention to prepare immediately to be detected by liquid chromatography.
Testing conditions: instrument: Agilent 1100 high performance liquid chromatograph;
Chromatographic column: Luna C18,4.6mm × 250mm, 5 μm;
Column temperature: 25 DEG C;
Flow velocity: 1.0mL/min;
Determined wavelength: 210nm;
Sampling volume: 5ul;
Moving phase: acetonitrile: 0.1% phosphate aqueous solution=60:40 (v/v);
Working time: 25min.
After detecting, as shown in Figure 1, analytical results is as shown in table 1 for the liquid chromatogram of sample.
Table 1: (the R)-4-aminophenethyl adopting synthetic method of the present invention to obtain-(2-hydroxyl-2-styroyl)-t-butyl carbamate sample chromatogram analytical results
As can be seen from Fig. 1 and table 1: (the R)-4-aminophenethyl adopting synthetic method of the present invention to prepare-(2-hydroxyl-2-styroyl)-t-butyl carbamate purity is higher, reaches 99.29%.
(R)-4-aminophenethyl-(2-hydroxyl-2-the styroyl)-t-butyl carbamate sample adopting synthetic method of the present invention to prepare is carried out hydrogen nuclear magnetic resonance spectrum analysis.
Specific embodiment described herein is only to the explanation for example of the present invention's spirit.Those skilled in the art can make various amendment or supplement or adopt similar mode to substitute to described specific embodiment, but can't depart from spirit of the present invention or surmount the scope that appended claims defines.
Although made a detailed description the present invention and quoted some specific embodiments as proof, to those skilled in the art, only otherwise it is obvious for leaving that the spirit and scope of the present invention can make various changes or revise.
Claims (4)
1. the synthetic method of (R)-4-aminophenethyl-(2-hydroxyl-2-styroyl)-t-butyl carbamate, it is characterized in that, this synthetic method comprises the following steps:
S1, oxidizing reaction: under the protection of nitrogen, p-nitrophenyl ethanol and adjacent iodoxybenzoic acid are added forming reactions liquid in ethyl acetate, by reaction solution return stirring to reacting completely, reaction solution after reacting completely is down to room temperature, suction filtration obtains filter cake and filtrate, washing leaching cake, merging, concentrated filtrate obtain p-nitrophenyl acetaldehyde; The mol ratio of described adjacent iodoxybenzoic acid and p-nitrophenyl ethanol is 2.5:1;
S2, reduction amination: above-mentioned obtained p-nitrophenyl acetaldehyde is carried out reductive amination process with (R)-2-amino-1-phenylethyl alcohol under the effect of sodium borohydride, make the amino on (R)-2-amino-1-phenylethyl alcohol and the aldehyde radical dehydrating condensation on p-nitrophenyl acetaldehyde, after reduction, obtain (R)-2-p-nitrophenyl ethylamino--1-phenylethyl alcohol; Described sodium borohydride is 2:1 with the mol ratio of (R)-2-amino-1-phenylethyl alcohol;
S3, substitution reaction: by above-mentioned obtained (R)-2-p-nitrophenyl ethylamino--1-phenylethyl alcohol and (Boc)
2o reacts, and makes amino quilt (Boc) on (R)-2-p-nitrophenyl ethylamino--1-phenylethyl alcohol
2o replaces (R)-4-nitrophenethyl-(2-hydroxyl-2-styroyl)-t-butyl carbamate; Described (Boc)
2o is 1.5:1 with the mol ratio of (R)-2-p-nitrophenyl ethylamino--1-phenylethyl alcohol;
S4, reduction reaction: above-mentioned obtained (R)-4-nitrophenethyl-(2-hydroxyl-2-styroyl)-t-butyl carbamate is dissolved in anhydrous methanol, under the effect of palladium charcoal and hydrogen, make the nitro on (R)-4-nitrophenethyl-(2-hydroxyl-2-styroyl)-t-butyl carbamate be reduced into amino, obtain final product (R)-4-aminophenethyl-(2-hydroxyl-2-styroyl)-t-butyl carbamate.
2. the synthetic method of (R)-4-aminophenethyl according to claim 1-(2-hydroxyl-2-styroyl)-t-butyl carbamate, it is characterized in that, described step S2 specifically comprises the steps: under the protection of nitrogen, the methylene dichloride being dissolved with p-nitrophenyl acetaldehyde obtained in step S1 is added drop-wise to forming reactions liquid in (R)-2-amino-1-phenylethyl alcohol, under stirring, sodium borohydride is joined in reaction solution, be stirred to and react completely, saturated aqueous ammonium chloride is added drop-wise in the reaction solution reacted completely and carries out cancellation reaction, wash with water again, separate organic phase, organic phase is dry, concentrate to obtain crude product, crude product recrystallization obtains (R)-2-p-nitrophenyl ethylamino--1-phenylethyl alcohol.
3. the synthetic method of (R)-4-aminophenethyl according to claim 1-(2-hydroxyl-2-styroyl)-t-butyl carbamate, it is characterized in that, described step S3 specifically comprises the steps: (R)-2-p-nitrophenyl ethylamino--1-phenylethyl alcohol obtained in step S2 to be dissolved in tetrahydrofuran (THF), stirs lower to (Boc)
2o is added drop-wise in tetrahydrofuran (THF), reaction solution is risen to room temperature, be stirred to and react completely, the reaction solution reacted completely directly is concentrated to obtain crude product, and crude product recrystallization obtains final product (R)-4-nitrophenethyl-(2-hydroxyl-2-styroyl)-t-butyl carbamate.
4. the synthetic method of (R)-4-aminophenethyl according to claim 1-(2-hydroxyl-2-styroyl)-t-butyl carbamate, it is characterized in that, step S4 specifically comprises the steps: (R)-4-nitrophenethyl-(2-hydroxyl-2-styroyl)-t-butyl carbamate obtained in step S3 to be dissolved in solvent forming reactions liquid, under the effect of catalyzer and hydrogen, under the condition of room temperature, stirring reaction liquid is to reacting completely, solubilizing agent dilute reaction solution, use filtered off through Celite catalyzer, the filtrate of gained is concentrated to obtain (R)-4-aminophenethyl-(2-hydroxyl-2-styroyl)-t-butyl carbamate.
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| Microwave-assisted synthesis of 5-substituted 2-aminothiophenes starting from arylacetaldehydes;Germain Revelant et al;《Synthesis》;20110805(第18期);2935-2940 * |
| Synthesis and Evaluation of Novel Phenylethanolamine Derivatives containing Acetanilides as Potent and Selective β3-Adrenergic Receptor Agonists;Tatsuya Maruyama et al;《Chem. Pharm. Bull.》;20100127;第58卷(第4期);533-545 * |
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